American Journal of Medical Genetics 68:7–11 (1997)

© 1997 Wiley-Liss, Inc.

XY Gonadal Dysgenesis Associated With a Multiple Pterygium Syndrome Phenotype

Brad Angle,1* Joseph H. Hersh,1 Frank Yen,1 and Gerald D. Verdi2

1 Department of Pediatrics, Child Evaluation Center, University of Louisville, Louisville, Kentucky2 Department of Surgery, Child Evaluation Center, University of Louisville, Louisville, Kentucky

Most phenotypic females with an XY malekaryotype do not have significant extra-genital anomalies; however, some patientswith additional abnormalities have been de-scribed. We report on an individual with XYgonadal dysgenesis, mental retardation, microcephaly, growth retardation, and mul-tiple pterygia. Although not previously re-ported, the possible relationship betweenthese findings is discussed in the context of evident heterogeneity of XY gonadal dysgenesis. Am. J. Med Genet. 68:7–11, 1997© 1997 Wiley-Liss, Inc.

KEY WORDS: XY gonadal dysgenesis; mul-tiple pterygium; phenotype

INTRODUCTIONSex differentiation is a complex physiologic process

that most likely involves the products of many genes,not only on the Y chromosome, but also several that areX-linked and autosomal. Much of the information re-garding the mechanisms involved in normal sex deter-mination has been obtained from the studies of individ-uals with a defect of this process: phenotypic maleswith a female karyotype (46,XX) and phenotypic fe-males with a male karyotype (46,XY).

Following the discovery that the Y chromosome wasnecessary for normal male sexual differentiation, a spe-cific gene (SRY) on the short arm of the Y chromosomewas identified that is required for initiation of thetestis-determining pathway. Autosomal and X-linkedloci also have been implicated in the pathway of normalsex determination. There may be a number of still un-known genes that play a role in sex differentiation.

XY gonadal dysgenesis is one form of sex reversal(Swyer syndrome) in which affected individuals arephenotypic females with a uterus and fallopian tubes,

but only remnants of ovaries, i.e., streak gonads. Mostof these individuals are otherwise normal and do nothave somatic anomalies. However, a number of XY fe-males have been reported to have nongenital anom-alies; of these, none has been described with features ofmultiple pterygia.

The multiple pterygium phenotype is characterizedby flexion contractures at birth associated with vari-able webbing of the neck, elbows, knees, and intra-crural areas. Although digital and vertebral abnormal-ities, short stature, and facial anomalies are commonfindings, visceral anomalies are not. Intelligence in af-fected individuals is normal. Some cases appear to dem-onstrate an autosomal recessive inheritance pattern;however, autosomal dominant cases have been iden-tified.

We report on a patient with XY gonadal dysgenesisand multiple pterygia. A brief summary of these condi-tions and the implications of their coexistence in thesame patient are discussed.

CLINICAL REPORT

At term, a female infant was born to a 28-year-oldG2P1 mother after an uncomplicated pregnancy andvaginal delivery. There was no consanguinity. A malehalf-sib (maternal) had a unilateral clubfoot. The in-fant had a weight of 3.7 kg (75th centile), length 51 cm(50th centile), and head circumference (OFC) 39 cm(.90th centile). There was asymmetry of the calvariaand frontal bossing. A double parietal hair whorl wasnoted. The ears were small and apparently low-set withoverfolded helices. There was micrognathia. The neckwas short with anterior webbing. Skin dimpling waspresent over the elbows. There was subcutaneous syn-dactyly between the second and third digits and thirdand fourth digits of both hands, clinodactyly of thegreat toes, second and fifth fingers, and fifth toes. Aright single palmar crease and a left bridged palmarcrease were noted. There was webbing of both elbowswith limited extension. The sternum was short and theshoulders were anteriorly rotated. Contractures of theshoulders, knees, and ankles were present, and therewas some limitation of thumb extension. The externalgenitalia appeared to be normal. Neurological examshowed generalized hypotonia.

*Correspondence to: Brad Angle, M.D., Child Evaluation Cen-ter, University of Louisville, 571 S. Floyd St, Suite 100, Louisville,KY 40202.

Received 16 May 1995; Accepted 8 April 1996

Chromosome analysis performed on cultured leuko-cytes using both G- and Q-banding techniques showeda 46,XY karyotype in 20 metaphases analyzed. This46,XY karyotype was also present in 40 metaphases ofcultured fibroblasts. The Xp21 region appeared intact,with no evidence of duplication. Skeletal survey andMRI of the brain were normal. Vaginogram and voidingcystourethrogram demonstrated a uterus and normalurethra. At 15 months, the patient had a laparotomy toremove the gonads. Normal Fallopian tubes and uteruswere present. Histologic examination of the gonads doc-umented “streak” gonads consisting of ovarian stromawithout evidence of oocytes.

She was re-examined at 9 years (Fig. 1). Her weightwas 17 kg (,5th centile; 50th centile for 5 years);height 109 cm (,5th centile; 50th centile for 4 years).Multiple pterygia of the neck, axilla, elbows, knees, andinterdigital spaces of the fingers and toes were present.There was mild left facial asymmetry with a broad fore-head, ptosis of the eyelids, deviation of the nose to theleft, and micrognathia. The ears were apparently low-set and posteriorly angulated. There was mild clitoro-megaly and the labia were hypoplastic. Skin dimpleswere present in the presacral area and on the lateralaspects of both buttocks. An exaggerated lumbar lordo-sis was noted. She had unintelligible speech; however,she was able to communicate to some degree by signing.

Intellectual abilities were in the moderate range ofmental retardation.

Molecular studies using PCR with DNA primers flank-ing multiple regions of the Y chromosome confirmedthat there was no deletion. Portions of the SRY gene located in the conserved DNA-binding domain high mo-bility group (HMG)-box were sequenced and no muta-tion was detected.

Fluorescence in situ hybridization (FISH) studieswere performed using microsection slides of paraffin-embedded left and right ovaries obtained from priorsurgery. A control testis and a control ovary were alsostudied. Cells were hybridized with X and Y chromo-some probes (VYSIS Tri-Color CEP mixture 18 SA/XSG/Y SO, #32-111065, Lot/Ch.-B: 4309). FISH analysisof the patient’s left and right ovaries revealed the pres-ence of one green signal for one X chromosome and oneorange signal for one Y chromosome in each cell.

DISCUSSIONNormal human sex differentiation consists of three

basic steps [Jost, 1953, 1960, 1972]. Each of these stepsinvolves a number of complex, sequential processes.The first step is the establishment of genetic sex, whichis determined at fertilization. In the second step an in-different gonad differentiates into a testis in the XYmale or an ovary in the XX female. In the absence of the

8 Angle et al.

Fig. 1. a,b,c: Nine-year-old girl with XY gonadal dysgenesis and webbing of the neck, elbows, andknees, joint contractures, camptodactyly, ptosis, and downslanted palpebral fissures, mild facial asym-metry, and posteriorly angulated, apparently low-set ears.

Y chromosome, a testis-determining pathway fails to beinitiated or is blocked, and development of the fetalgonads follows an inherent ovarian pathway. Testis development from the embryonic bipotential gonad de-pends on the inheritance of a Y chromosome-encodedgene, which was previously referred to as the testis-determining factor (TDF) and subsequently identifiedas the SRY (sex-determining region Y) gene [Sinclair et al., 1990]. SRY most likely activates a succession ofother genes that switch the inherently female patternof development to that of the male, beginning withtestis formation. The final step in the pathway of nor-mal sexual differentiation, the translation of gonadalsex into phenotypic sex, depends on the type of gonadformed. Indifferent internal and external genital pre-cursors are converted to male or female structures, depending on whether or not a testis develops (with notable exceptions exemplified by the testicular femi-nization syndrome). Hormones produced by the fetaltestis are responsible for the induction of masculiniza-tion of the external genitalia and development of thestructures of the male reproductive tract, as well asprevention of the development of the uterus and fallo-pian tubes.

XY gonadal dysgenesis (also referred to as “pure XY”gonadal dysgenesis) is a disorder in which phenotypicfemales have a 46,XY chromosomal complement. Fail-ure of testicular differentiation occurs in genetic males,resulting in nonvirilized female external genitalia andpersistent Müllerian derivatives, including uterus,cervix, and Fallopian tubes. The oocytes of these pa-tients degenerate, resulting in atresia of the follicles.The gonadal remnants persist as “streaks” of connec-tive tissue. These “streak” gonads have a high risk ofneoplastic transformation.

Swyer [1955] was the first author to document casesof XY gonadal dysgenesis, and this condition was ini-tially referred to as Swyer syndrome. Over 120 cases ofXY gonadal dysgenesis have been reported [Bercu andSchulman, 1980]. Sporadic cases occur, but many havebeen familial, compatible with autosomal recessive inheritance limited to karyotypic males or X-linked recessive inheritance [Simpson et al., 1971; German et al., 1978; Nazareth et al., 1979; Hersh et al., 1980;Phansey et al., 1980; Simpson et al., 1981].

The pathogenesis of the XY gonadal dysgenesis phe-notype appears to be heterogeneous, resulting from avariety of defects in the testis-determining/differentia-tion pathway. Some XY females with gonadal dysgen-esis have lost the sex-determining region of the Y chromosome by terminal exchange between the sexchromosomes [Levilliers et al., 1989] or by other dele-tions [Page et al., 1990]. Approximately 10–15% of sex-reversed XY females without a Y chromosome deletionhave mutations in the SRY gene [Berta et al., 1990;Jager et al., 1990; Hawkins, 1993; Guidozzi et al., 1994;Schmitt-Ney et al., 1995]. With one exception [Tajimaet al., 1994], SRY mutations cluster in the DNA seg-ment encoding the high mobility group domain of theSRY protein [Schmitt-Ney et al., 1995]. In other cases,the phenotype may result from mutations in the regu-latory regions of the SRY gene [Schmitt-Ney et al.,

1995], or X-chromosomal or autosomal mutations ingenes involved in sex determination downstream ofSRY in the testis-determining pathway.

X-linked genes have been implicated in several fa-milial cases of XY gonadal dysgenesis. Duplication ofthe Xp21 region causes sex reversal and multiple con-genital abnormalities including mental retardation[Arn et al., 1994; Bardoni et al., 1994]. The severity ofthe abnormalities appears to depend upon the extent of the duplication. An autosomal sex reversal locus,SRA1, has been identified in XY females with cam-pomelic syndrome [Tommerup et al., 1993]. Another autosomal sex reversing gene is located on 9p [Bennett et al., 1993]. A gene that regulates SRY has not yetbeen discovered. Regulation of SRY may involve the au-tosomal or X-linked genes described, or an unknown lo-cus. Thus, XY gonadal dysgenesis is a heterogeneousphenotype.

Whereas most individuals with XY gonadal dysgene-sis have a normal female phenotype and do not haveother anomalies, some patients with extragenital ab-normalities have been reported. Simpson et al. [1981]reported XY gonadal dysgenesis associated with cam-pomelic dysplasia and with renal disorders. Simpson et al. [1982] later described a patient with XY gonadaldysgenesis, myotonic dystrophy, and end-stage renaldisease. Moorthy et al. [1987] reviewed six previouslyreported patients with XY gonadal dysgenesis and re-nal failure and suggested the term “Frasier syndrome”after Frasier et al. [1964], who described two affectedpatients in 1964.

Gardner et al. [1970] reported on a 46,XY femalewith cleft palate, micrognathia, kyphoscoliosis, andclubfoot. Subsequently, Greenberg et al. [1987] re-viewed these and 11 additional patients and suggestedthat they represented a recognizable syndrome thatmight be inherited in an autosomal recessive or X-linked recessive manner and designated it as the Gardner-Silengo-Wachtel or genito-palato-cardiac syn-drome. Brosnan et al. [1980] described two 46,XY sis-ters with unusual face, cardiac, renal, musculoskeletal(acromelia with broad hands and feet, hypermuscularappearance), and ectodermal (scalp defects and un-usual whorl patterns) anomalies. Silengo et al. [1974]described a 46,XY female infant with minor anomaliesand limb abnormalities.

Our patient had a female phenotype with multiplepterygia. In their review, Hall et al. [1982] described 15entities with limb pterygia, including autosomal domi-nant and recessive disorders.

The earliest complete description of one of these con-ditions, multiple pterygium syndrome, is generallycredited to Matolscy [1936]. The designation multiplepterygium syndrome was used by Gorlin et al. [1976] todescribe an autosomal recessive disorder that is char-acterized by pterygia of the neck, antecubital, andpopliteal areas; syndactyly of the fingers; numerouscongenital joint contractures; and talipes equinovarus.Other anomalies may include vertebral segmentationanomalies, scoliosis, and short stature. Multiple minorfacial anomalies are present in most cases, includingdownward-slant of palpebral fissures, epicanthal folds,and ptosis. Intelligence is normal in these patients.

XY Gonadal Dysgenesis and Multiple Pterygium 9

Chen et al. [1980] emphasized the heterogeneity ofmultiple pterygium phenotype. Although most casesappear to be due to autosomal recessive inheritance,autosomal dominant cases have been documented [Fríaset al., 1973; McKeown and Harris, 1988]. With the ex-ception of a case of 47,XXY/48,XXXY mosaicism withmultiple joint webbing, aniridia, and mental retarda-tion [Pashayan et al., 1973], no chromosome abnormal-ities have been reported in patients with multiplepterygium syndrome.

Multiple pterygia, facial anomalies, and joint con-tractures are common to all forms of multiple pteryg-ium syndrome. In contrast to normal intellect in the au-tosomal recessive form, mental retardation has beendescribed in some patients with the autosomal domi-nant form.

Our patient appears to be the first reported case ofXY gonadal dysgenesis associated with multiple pte-rygia. It is possible that in this case, the nongenital ab-normalities are coincidental. Therefore, the existenceof two genetic disorders, including both XY gonadaldysgenesis and an autosomal dominant form of multi-ple pterygium syndrome in which mental retardation isa component in the same patient, cannot be excluded.However, since XY gonadal dysgenesis can be associ-ated with other anomalies, or be part of recognizableconditions, heterogeneity of XY gonadal dysgenesismay exist. Therefore, in our patient, the presence of XYgonadal dysgenesis, multiple pterygia, short stature,microcephaly, and mental retardation may represent anew syndrome. Since no deletion in the Y chromosomeor mutation in the SRY gene was detected in our patient, an unknown X-linked or autosomal gene in-volved in the sex-determination pathway may havebeen responsible for causing both XY gonadal dysgene-sis and the phenotype of multiple pterygium, growthdeficiency, microcephaly, and mental retardation. Iden-tification of other patients with XY gonadal dysgenesisand similar nongenital anomalies would support thepremise that these conditions may be related patho-genetically.

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